Use of polygenic and clinical risk scores in wide spectrum congenital heart malformations: a diagnostic and therapeutic perspective


  • Sana Ashiq Institute Of Industrial Biotechnology, Government College University, Lahore, Pakistan
  • Kanwal Ashiq Superior University, Lahore, Pakistan
  • Asad Ur Rehman Institute Of Industrial Biotechnology, Government College University, Lahore, Pakistan



Worldwide, congenital heart defects (CHDs) are a leading cause of mortality and morbidity. Globally, the annual prevalence rate of CHDs is about 1.5 million. It is one of the most common life-threatening congenital malformations, with a visible difference between high-income countries (HICs) and developing countries. This difference may be attributed to the diagnostic facilities and interventions.1 Moreover, the use of genetic and clinical risk scores is less studied in this field compared to other diagnostic and therapeutic approaches. Thus, we comprehensively review the available literature on adult and pediatric syndromic or non-syndromic CHDs and propose limitations and future directions in this field. Risk factors for this fatal disease include genetic and environmental factors.2,3 Risk stratification based on prenatal diagnosis with genetic counseling has shown better clinical outcomes. The modified World Health Organization (mWHO) guidelines are among the first proposed for risk stratification based on clinical scores.4 The combination of polygenic risk scores (PRS) and clinical risk evaluation has been adopted in various populations as better diagnostic and therapeutic approaches for various diseases, including coronary artery disease,5 diabetes,6 obesity,7 and cancers.8,9 However, unlike these diseases, polygenic risk scores are rarely used for the genetic diagnosis of CHD patients. The clinical utility of polygenic risk scores for CHDs is still in the early stages and requires validation studies in different cohorts. Incorporating PRS into the clinical setting may improve CHD diagnosis and therapeutic strategies.10 Recently, an initial attempt was made to determine the clinical utility of polygenic risk scores in a large dataset of the European cohort. Data from this study suggested a high potential for PRS in distinguishing between clinical phenotypes (mild, moderate, and severe) of congenital heart malformations.11 Furthermore, this hypothesis was tested in patients with transposition of the great arteries (TGA) to assess the utility of risk stratification after arterial switch operation. The cumulative risk score was computed for single nucleotide polymorphisms (SNPs) that reached the threshold statistical significance of p<1×10−5 in the initial analysis. Combined clinical and polygenic risk scores showed improved risk stratification in mild, moderate, and severe TGA phenotypes.12 Similarly, in another European cohort, the risk allele frequency was higher in the diseased group compared to the control group. However, statistical analysis suggested a non-significant association with p>0.05. Interestingly, combined risk scores constructed for selected SNPs showed a significant association with the disease with a p-value of 0.002. This evidence further supports the hypothesis that the cumulative effect of polymorphisms has better diagnostic and therapeutic efficacy than individual SNPs.13 There are certain limitations to its clinical use. Firstly, social stigma and lack of awareness regarding this disease are major hurdles. Secondly, there is a need to recruit a large number of samples from different populations to validate the clinical utility of PRS. Additionally, a lack of resources in developing countries also contributes to fatal outcomes. We recommend conducting large cohort studies in different ethnic groups to predict better risk associations, develop better therapeutic strategies, and formulate management guidelines.


  1. Zuhlke L, Lawrenson J, Comitis G, De Decker R, Brooks A, Fourie B, et al. Congenital heart disease in low-and lower-middle–income countries: current status and new opportunities. Curr Cardiol Rep. 2019;21(12):163.
  2. Zhang TN, Wu QJ, Liu YS, LV JL, Sun H, Chang Q, et al. Environmental risk factors and congenital heart disease: an umbrella review of 165 systematic reviews and meta-analyses with more than 120 million participants. Front Cardiovasc Med. 2021;8:
  3. Diab NS, Barish S, Dong W, Zhao S, Allington G, Yu X, et al. Molecular genetics and complex inheritance of congenital heart disease. Genes. 2021;12(7):1020.
  4. Van Hagen IM, and Roos-Hesselink JW. Pregnancy in congenital heart disease: risk prediction and counselling. Heart. 2020;106(23):1853-61.
  5. Shabana NA, Ashiq S, Ijaz A, Khalid F, Khan K, Sarwar S, et al. Genetic risk score (GRS) constructed from polymorphisms in the PON1, IL-6, ITGB3, and ALDH2 genes is associated with the risk of coronary artery disease in Pakistani subjects. Lipids Health Dis. 2018;17(1):224.
  6. Shitomi-Jones LM, Akam L, Hunter D, Singh P, and Mastana S. Genetic risk scores for the determination of type 2 diabetes mellitus (T2DM) in North India. Int J Environ Res Public Health. 2023;20(4):3729.
  7. Dashti HS, Miranda N, Cade BE, Huang T, Redline S, Karlson EW, et al. Interaction of obesity polygenic score with lifestyle risk factors in an electronic health record biobank. BMC Med. 2022;20(1):5.
  8. Conran CA, Shi Z, Resurreccion WK, Na R, Helfand BT, Genova E, et al. Assessing the clinical utility of genetic risk scores for targeted cancer screening. J Transl Med. 2021;19:1-9.
  9. Byrne S, Boyle T, Ahmed M, Lee SH, Benyamin B, Hypponen E. Lifestyle, genetic risk and incidence of cancer: a prospective cohort study of 13 cancer types. Int J Epidemiol. 2023;52:817-26.
  10. Morrish AM, Smith J, Enriquez A, Sholler GF, Mervis J, Dunwoodie SL, et al. A new era of genetic testing in congenital heart disease: a review. Trends Cardiovasc Med. 2022;32:311-9.
  11. Spendlove SJ, Bondhus L, Lluri G, Sul JH, and Arboleda VA. Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease. Hum Genet Genom Adv. 2022;3(3):100112.
  12. Woudstra OI, Skoric-Milosavljevic D, Mulder BJ, Meijboom FJ, Post MC, Jongbloed MR, et al. Common genetic variants improve risk stratification after the atrial switch operation for transposition of the great arteries. Int J Cardiol. 2023;371:153-9.
  13. Borghini A, Vecoli C, Mercuri A, Turchi S, and Andreassi MG. Individual and joint effects of genetic polymorphisms in microRNA-machinery genes on congenital heart disease susceptibility. Cardiol Young. 2021;31(6):965-8.


Download data is not yet available.




How to Cite

Ashiq S, Ashiq K, Rehman AU. Use of polygenic and clinical risk scores in wide spectrum congenital heart malformations: a diagnostic and therapeutic perspective. Pak Heart J [Internet]. 2024Mar.30 [cited 2024Jun.16];57(1):75-6. Available from:



Short Communication